TGF-β Superfamily Signaling

The TGF-β superfamily consists of over 30 structurally related members. The proteins encoded by TGF-β superfamily genes are processed to produce mature peptides by proteolytic cleavage. The TGF-β superfamily signaling begins with the secretion of TGF-β ligand peptides. These peptides are dimerized into homodimers or heterodimers and are secreted from the cell. Secreted dimers bind to their respective type I and type II serine/threonine kinase receptors and elicit transcriptional responses through phosphorylation of the receptors-regulated Smad proteins (R-Smads). In vertebrates, the type I receptors for bone morphogenetic proteins (BMPs) phosphorylate Smad1 or the closely related Smad5 and Smad8; whereas the type I receptors for TGF-βs, Activins and Nodal signal through Smad2 and Smad3. Phosphorylated R-Smads form heteromeric complexes with a common Smad, Smad4, and translocate into the nucleus to regulate target gene expression. Diverse nuclear DNA binding proteins interact with R-Smad/Smad4 complexes in the nucleus, mediating cell type-specific responses to TGF-β signaling.

There are three types of TGF-β superfamily receptors on the surface of cell membrane: type I receptor, type II receptor, and co-receptor. In TGF-β superfamily signaling, there are 3 models of ligand binding to receptors:

1. Ligand binds to the co-receptor, which presents the ligand to the type II receptor. The type II receptor then activates the type I receptor. This model has been found in TGF-β subfamily signaling.

2. Ligand binds to the type II receptor and then activates the type I receptor to the signaling complex. This model has been found in TGF-β subfamily and Activins signaling.

3. The type I and type II receptors bind ligand in a cooperative manner, meaning the two receptors have a much higher affinity when together than they do individually. This model has been found in BMPs signaling.

TGF-β superfamily signaling can be regulated at different levels, including the ligand, the receptors and the Smad. At the level of the Smad, the linker region of R-Smad is phosphorylated by mitogenactivated protein kinase (MAPK), resulting in the inhibition of nuclear accumulation of Smad complexes. There are also 2 intracellular inhibitory Smads: Smad 6 which inhibits BMP signaling and Smad 7 which inhibits TGF-β signaling.

Several types of mechanisms have evolved to limit signaling mediated by TGF-βs. One major mechanism for regulating TGF-β signaling is via the action of secreted protein antagonists. These proteins, including Noggin, Chordin, Follistatin and DAN/Cerberus, bind to TGF-βs to inhibit receptor binding or receptor activation. For example, Follistatin, a potent Activin antagonist, neutralizes the ligand by masking one-third of its residues and its receptor binding sites. Structural analyses have shown that Follistatin’s N-terminal domain has a specific fold that mimic a universal type I receptor motif, occupying the receptor binding site of the TGF-β ligand.

TGF-β signal transduction can also by modulated at the membrane by BAMBI (BMP and Activin membrane bound inhibitor), a TGF-β pseudo receptor, that plays a role in attenuating BMP, Activin, and TGF-β signaling.